Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

Vivek Thumbigere-Math, Brian L. Foster, Mahesh Bachu, Hiroaki Yoshii, Stephen R. Brooks, Alyssa Coulter, Michael B. Chavez, Sumihito Togi, Anthony L. Neely, Zuoming Deng, Kim C. Mansky, Keiko Ozato, Martha J. Somerman

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This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8G388S) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8G388S mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8WT control. Further, similar to subjects with heterozygous IRF8G388S mutation, Irf8+/– mice exhibited increased osteoclast activity in the mandibular alveolar bone surrounding molar teeth. Immunohistochemistry illustrated increased NFATc1 expression in the dentoalveolar region of Irf8–/– and Irf8+/– mice when compared with Irf8+/+ controls. Genomewide analyses revealed that IRF8 constitutively bound to regulatory regions of several thousand genes in osteoclast precursors, and genetic aberration of IRF8 significantly enhanced many osteoclast-specific transcripts. Collectively, this study delineates the critical role of IRF8 in defining osteoclast lineage and osteoclast transcriptional program, which may help in better understanding of various osteoclast-mediated disorders, including periodontal disease.

Original languageEnglish (US)
Pages (from-to)1155-1168
Number of pages14
JournalJournal of Bone and Mineral Research
Issue number6
StatePublished - Jun 2019




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Thumbigere-Math, V., Foster, B. L., Bachu, M., Yoshii, H., Brooks, S. R., Coulter, A., Chavez, M. B., Togi, S., Neely, A. L., Deng, Z., Mansky, K. C., Ozato, K., & Somerman, M. J. (2019). Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption. Journal of Bone and Mineral Research, 34(6), 1155-1168.